Adult T-cell leukemia/lymphoma (ATL) is an aggressive proliferation of mature activated CD4+ T cells associated with the human T-cell lymphotropic virus type I (HTLV-I). Leukemia develops after a very long latency period and is preceded by oligoclonal expansions of HTLV-I-infected activated T cells. These clonal expansions result from the expression of the viral transactivator protein Tax, which activates various cellular genes and creates an autocrine loop involving interleukin-2, interleukin-15, and their cognate receptors. The diversity in clinical features and prognosis of ATL patients has led to its subclassification into smoldering, chronic, lymphoma, and acute subtypes. Patients with aggressive ATL (acute and lymphoma subtypes) generally have a very poor prognosis because of intrinsic chemoresistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications due to a profound T-cell immune deficiency. Patients with indolent ATL (ie, the chronic or smoldering subtypes) have a better prognosis. However, data from Japan showed poor long-term survival results when these patients are managed with a watchful-waiting policy until disease progression or with chemotherapy. Indeed, 4-year survival in chronic ATL is less than 30%.
It was shown that high response rates are achieved in ATL patients with the combination of the antiretroviral nucleotide analog zidovudine (AZT) and interferon alpha (IFN) (Gill P S, Harrington W Jr, Kaplan M H, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995; 332:1744-1748; Hermine O, Bouscary D, Gessain A, et al. Brief report: treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa. N Engl J Med. 1995; 332:1749-1751; Bazarbachi A, Hermine O. Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 13(suppl 1):S186-S190; White J D, Wharfe G, Stewart D M. et al. The combination of zidovudine and interferon alpha-2B in the treatment of adult T-cell leukemia/lymphoma. Leuk Lymphoma. 2001; 40:287-294; Hermine O, Allard I, Lévy V, et al. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J. 2002; 3:276-282; Matutes E, Taylor G P, Cavenagh J, et al. Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. Br J Haematol. 2001; 13:779-784). However, most patients eventually relapse, which underlines the need for new therapeutic approaches.
Arsenic trioxide (As) is a very effective treatment of acute promyelocytic leukemia (APL), a distinct subtype of acute mycloid leukemia that is characterized by unique clinical characteristics and a specific cytogenctic abnormality, t(15; 17), which results in a reciprocal translocation between the PML gene on chromosome 15 and the retinoic acid receptor α (RAR-α) gene on chromosome 17. Clinically, As directly targets and degrades PML/RARA fusion protein, inducing clinical remission of APL patients.
In ATL cell-lines, we have previously shown that As synergizes with IFN to induce cell cycle arrest and apoptosis (Bazarbachi A, EI-Sabban M E, Nasr R, et al. Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells. Blood. 1999; 93:278-283). At the molecular level, the combination of As/IFN specifically induces proteosomal degradation of the HTLV-1 oncoprotein Tax and reversal of NF-κB activation (EI-Sabban M E, Nasr R, Dbaibo G, et al. Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation. Blood. 2000; 96:2849-2855; Nasr R, Rosenwald A, El-Sabban M E, et al. Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells. Blood. 2003; 101:4576-4582). Such specific targeting of the viral oncoprotein by IFN/As treatment, reminiscent of As targeting of PML/RAR in APL, provides strong rational for combined IFN/As therapy in ATL patients. In that sense, it was previously reported the results of a phase 2 trial of As/IFN combination in 7 patients with relapsed/refractory aggressive ATL after AZT, IFN, and chemotherapy (Hermine O, Dombret H, Poupon J, et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol J. 2004; 5:130-134). One patient achieved complete remission, 3 achieved partial remission, and 3 progressed. The patient in complete remission (CR) is still alive after more than 5 years of follow up. These results indicate that treatment with As and IFN is feasible and exhibits an antileukemic effect in vivo in these selected aggressive ATL patients with poor prognosis. Similarly, a transient response to As/IFN combination was reported in Japan in 2 patients with refractory acute ATL (Ishitsuka K, Suzumiya J, Aoki M, Ogata K, Hara S, Tamura K. Therapeutic potential of arsenic trioxide with or without interferon-alpha for relapsed/refractory adult T-cell leukemia/lymphoma. Haematologica. 2007; 92:719-720).